


EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: Kerry Leifer 703-308-8811


Ecolab Inc.

[IN-11307]

	EPA has received a pesticide petition ([IN-11307]) from Ecolab Inc., 1 Ecolab Place, St. Paul, MN 55102 requesting, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180
   
   	1. to establish an exemption from the requirement of a tolerance for
   

	Dipicolinic acid when used as an inert ingredient in pesticide formulations applied to growing crops under 40 CFR 180.910 and to hard, non-porous food-contact surfaces in public eating places, dairy processing equipment, and food-processing equipment and utensils, according to 40 CFR 180.940(a) at an upper limit of 2 parts per million (ppm). EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of  FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry NA Remove.

	1. Plant metabolism. NA Remove

	2. Analytical method. NA Remove

	3. Magnitude of residues. NA Remove


B. Toxicological Profile

	1. Acute toxicity.  An acute oral LD50 >10,500 mg/kg was reported in rats, indicating low acute oral toxicity. An in-silico approach was also employed to estimate the acute oral LD50 using Collaborative Acute Toxicity Modeling Suite (CATMoS) v2.1 of the Open Structure-Activity/Property Relationship App (OPERA) QSAR tool. CATMoS predicted that DPA would be considered EPA Category III with an acute oral LD50 of 2884.9 mg/kg. Undiluted DPA is expected to be irritating to eyes and skin. A Derek Nexus analysis concluded that DPA does not match any structural alerts or examples for skin sensitization, nor does it contain any unclassified or misclassified features and is therefore predicted to be a non-sensitizer. 


	2. Genotoxicty. The mutagenic potential of DPA was measured in a reverse mutation assay in several strains of Salmonella typhimurium and Escherichia coli strain WP2 uvrA in the presence and absence of an exogenous metabolic activation system. Dimethyl Sulfoxide (DMSO) was used as the vehicle. Concentrations of 1.50, 5.00, 15.0, 50.0, 150, 500, 1500 and 5000 μg per plate produced no precipitate or definitive background lawn toxicity or positive mutagenic responses in either the presence or absence of S9 activation. These results indicate DPA is not mutagenic.

DPA was tested to evaluate its potential to induce structural chromosomal aberrations using human peripheral blood lymphocytes in both the absence and presence of an exogenous metabolic activation system using DMSO as the vehicle. Concentrations in the main assay ranged from 100 to 1670 μg/mL for the non-activated 4-hour exposure group, from 250 to 1250 μg/mL for the S9-activated 4-hour exposure group, and from 100 to 750 μg/mL for the non-activated 20-hour exposure group. Cytotoxicity was observed at dose levels >= 525 μg/mL in the non-activated 20-hour exposure group, but not in any other group or dose level. No significant or dose-dependent increases in structural or numerical aberrations were observed in treatment groups with or without S9 (p > 0.05; Fisher's Exact and Cochran-Annitage tests). These results indicate DPA does not induce structural or numerical chromosomal aberrations in the presence and absence of metabolic activation.

Derek-Nexus analysis found that DPA does not match any structural alerts or examples for mutagenicity in bacteria. 

	3. Reproductive and developmental toxicity. Derek Nexus did not detect any structural alerts for DPA related to reproductive toxicity, developmental toxicity, teratogenicity, or testicular toxicity. 

Additionally, the Threshold of Toxicological Concern (TTC) approach was used to evaluate the toxicity of DPA. DPA is a stabilizer that is effective at very low concentrations and has limited uses and therefore has a low dietary exposure, indicating that the TTC is a valid approach. Additionally, DPA has a limited dataset that does not include a subchronic or chronic study database that would allow a traditional risk assessment. Lastly, DPA does not fall into any of the exclusion categories that would preclude the use of TTC, which include substances not represented in the database or outside of the domain of applicability (e.g., inorganic substances, proteins, nanomaterials, radioactive substances, organo-silicon substances, metals in elemental, ionic or organic form), and substances with special properties (e.g. high potency carcinogens, substances with a potential for bioaccumulation).

The TTC approach is protective against developmental and reproductive effects. An analysis of a database of 283 chemicals indicated reproductive and developmental toxicity NOAELs were higher compared to the respective TTC values. A recent review of the TTC by the European Food Safety Authority (EFSA) concluded that the TTC values for Cramer Classes I and III are sufficiently protective for adverse effects on reproduction or development. 

	4. Subchronic toxicity. As a Cramer Class III substance, the TTC for DPA is 1.5 ug/kg/d. This is derived by applying a 100x uncertainty factor to the 5[th] % NOAEL, 0.15 mg/kg/day. All predicted DPA metabolites are also Cramer class III, so reliance on TTC would not be impacted by a difference in Cramer class for metabolites.

It could reasonably be argued that the use of the TTC value is more conservative than the use of a combined repeated dose toxicity study (OECD 422) to derive an RfD due to the following:
 High confidence (95%) that a NOAEL from a chronic study would be higher than 0.15 mg/kg/d for DPA;
 An RfD derived from an OECD 422 would be considered subchronic;
 The use of conservative uncertainty factors (100x);
 The broad coverage and robustness of the database used to derive TTC values;
 DPA's inclusion in the domain of applicability of the TTC database.

	5. Chronic toxicity. The TTC, 1.5 ug/kg/d, represents an RfD that would be derived with 95% confidence if a chronic study were executed with DPA and default uncertainty factors were utilized, indicating this approach is health-protective.  In addition, a Derek Nexus analysis did not detect any structural alerts for DPA related to carcinogenicity or genotoxicity. Furthermore, the US FDA Office of Food Additive Safety (OFAS) performed QSAR analyses of DPA using multiple statistical or rule-based systems designed to support ICH M7 guidelines to assess pharmaceutical impurities (MDL QSAR Genotoxicity prediction (Statistical); MDL QSAR Carcinogenicity (Statistical); MCASE Carcinogenicity (Statistical and Rule-Based); MCASE Genotoxicity/Mutagenicity (Statistical and Rule-Based); Derek Nexus for Windows (Rule-Based); Leadscope Genetox (Statistical and Rule-Based); Leadscope Rodent carcinogenicity (Statistical and Rule-Based)). All the models predicted that DPA was of low concern for both rodent carcinogenicity and mutagenicity; FDA OFAS concluded, "the overall analysis predicts that this structure [DPA] is not likely to be a strong mutagen or rodent carcinogen based on the software modules available to the QSAR team at the time of evaluation." Given the absence of carcinogenicity structural alerts, negative QSAR analyses, a negative bacterial reverse mutation assay, and a negative in vitro chromosomal aberration assay in human peripheral blood lymphocytes, it is unlikely that DPA is a carcinogen.

	6. Animal metabolism. The primary modifications taking place during DPA metabolism include aromatic hydroxylation and N-oxidation. 

	7. Metabolite toxicology. NA Remove

	8. Endocrine disruption. DPA was negative for endocrine disrupting activity in the ToxCast Pathway Model for androgen and estrogen as well as inactive as an agonist, antagonist, or binding in the Collaborative Estrogen Receptor Activity Prediction Project (CERAPP). DPA was screened against 232 targets in ToxCast; there were two weak hits for thyroid receptor α antagonism and nuclear factor κ B1 agonism, indicating low potential for reproductive or developmental effects.

C. Aggregate Exposure

	1. Dietary exposure. Aggregate sources of dietary exposure to DPA include the two new inert pesticide ingredient uses presented in this petition and the existing direct food sanitization uses regulated by US FDA. Using a conservative aggregate dietary assessment, exposure of the highest exposed population (children 1-2), does not exceed 1.5 ug DPA/kg bw/d, the TTC, which can also be considered the chronic population adjusted dose (cPAD).

Surface Sanitizer Use: Residue levels that may occur in food from application to food contact surfaces were estimated using American Chemistry Council Biocides Panel Food Contact Sanitizing Solutions in Commercial Settings Model, which assumes an application of 1 mg/cm2 surface area and surface area of 4000 cm[2]. This model predicted a dietary exposure of 24.24% of the cPAD for the most highly exposed subpopulation, children 1-2 years of age.

Agriculture Use: The dietary risk assessment for DPA use in pesticide formulations that may be applied to growing agricultural cops and raw agricultural commodities after harvest (40 CFR 180.910) was conducted using the conservative screening level dietary and drinking water exposure model for inert ingredients (I-DEEM). This conservative model assumes that 100% of all commodities, and 100% of all crops are treated with DPA. Using a conservative cap of 4 ppm DPA in formulations for I-DEEM calculations, which was increased from 2 ppm to account for uses on processed agricultural commodities, the highest dietary exposure estimate is 0.101% of the cPAD for the U.S. population and 0.369% for the most highly exposed subpopulation, children 1-2 years of age.

	i. Food. DPA is also used as a direct food sanitizer for beef, poultry, and seafood. Dietary exposure from these uses was conservatively estimated with use-levels dictated in relevant Food Contact Notifications (FCNs) and dietary data from NHANES. The dietary exposure estimate is 22.21% of the cPAD for the U.S. population and 73.7% for the most highly exposed subpopulation, children 1-2 years of age.
 

	ii. Drinking water. DPA exposure via drinking water from use as an inert ingredient is not expected to be significant. Based on the physical chemical characteristics of DPA, the compound is expected to biodegrade rapidly in water.  Exposure via the drinking water was estimated in the I-DEEM dietary exposure assessment assuming a concentration of 100 ppb.   

	2. Non-dietary exposure. NA Remove

D. Cumulative Effects

	Section 408(b)(2)(D) (9v) of the FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider "available information" concerning the cumulative effects of a particular pesticide's residues and "other substances that have a common mechanism of toxicity." To our knowledge there are no available data or other reliable information that suggests any toxic effects produced by DPA would be cumulative with those of any other chemical compounds. EPA has not made a common mechanism of toxicity finding as to DPA and other compounds. DPA does not appear to produce toxic metabolites in common with other substances of potential concern. For the purpose of the tolerance exemption proposed, it is assumed that DPA does not share a common mechanism of toxicity with other substances.


E. Safety Determination

	1. U.S. population. There is reasonable certainty that no harm to humans will result from the use of DPA as an inert ingredient intended for use at up to 2 ppm in antimicrobial formulations applied to food-contact surfaces in public eating places, dairy-processing equipment, food-processing equipment and utensils (40 CFR 180.940a) and applied to growing crops or to raw agricultural commodities pre- and post-harvest (40 CFR 180.910). As a Cramer Class III substance, the TTC for DPA is 1.5 ug/kg/d. This is derived by applying a 100x uncertainty factor to the 5[th] % NOAEL, 0.15 mg/kg/day, for Cramer Class III substances. The TTC represents a cPAD that would be derived with 95% confidence if a chronic study were executed with DPA and default uncertainty factors were utilized.

For the total US population, the estimated chronic dietary exposure to DPA from crops and drinking water is 0.101% of the cPAD and the estimated exposure from residues of surface sanitizers is 6.67% of the cPAD. These estimated exposures to DPA are well below any level of potential concern.

	2. Infants and children. There is a reasonable certainty that no harm to infants and children will result from the use of DPA as an inert ingredient intended for use at up to 2 ppm in antimicrobial formulations applied to food-contact surfaces in public eating places, dairy-processing equipment, food-processing equipment and utensils (40 CFR 180.940a) and applied to growing crops or to raw agricultural commodities pre- and post-harvest (40 CFR 180.910). DPA is not associated with developmental toxicity. The TTC of 1.5 ug/kg/day established for DPA is protective of infants and children.  Using a highly conservative model, the estimated chronic dietary exposure from residues of surface sanitizers was highest (24.24% of cPAD) for children aged 1 to 2 years old. The estimated dietary exposure from food crops and drinking water was also highest for children aged 1 to 2 years old, at 0.369% of the cPAD.  These estimated exposures to DPA are well below any level of potential concern.

F. International Tolerances

	NA Remove




